Hydroxyapatite tissue filler and its preparation and use

ABSTRACT

The invention pertains to a biocompatible composition, suitable for use in soft or hard tissue augmentation, wherein the composition is an aqueous suspension containing a carrier fraction of ceramic particles of less than 15 μm and an augmentation fraction of ceramic particles of at least 20 μm. The ceramics typically comprise calcium phosphate. The composition is a may be used in soft tissue repair as well as hard bone replacement. It advantageously avoids the need for foreign body materials which are conventionally applied to stabilize augmentation suspensions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.13/684,912, filed Nov. 26, 2012, which is a Continuation of U.S. patentapplication Ser. No. 12/444,514, filed Jun. 3, 2009, which is theNational Phase of International Patent Application No.PCT/NL2007/050479, filed Oct. 4, 2007, published on Apr. 10, 2008 as WO2008/041846 A2, which claims priority to U.S. Provisional PatentApplication No. 60/849,485, filed Oct. 5, 2006 and European PatentApplication No. 06121834.3, filed Oct. 5, 2006. The contents of theseapplications are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention pertains to biocompatible compositions containing ceramicparticles, in particular hydroxyapatite, for soft and hard tissueaugmentation, especially for bone regeneration and treatment of skincontour deficiencies, and for cosmetic use in plastic surgery, inparticular for filling soft tissue voids or creating soft tissueaugmentation.

BACKGROUND OF THE INVENTION

Since long biocompatible materials have been applied in augmenting softtissue in the practice of plastic and reconstructive surgery. Thesebiomaterials are commonly delivered to the tissue site whereaugmentation is desired by means of an injectable composition thatcomprises the biomaterial and a biocompatible fluid, wherein the fluidacts as a lubricant to improve the delivery of the biomaterialsuspension.

Since the mid-eighties polymethylmethacrylate (PMMA) has been studied asa soft tissue augmentation device, replacing then popular collagen. Thepermanent character of PMMA and many other fillers such as siliconeswould make repetitious corrections unnecessary. However, it isdiscovered recently that the injection of PMMA microspheres causes allkinds of complications in time, to a large extent related to thenon-biodegradable properties. Moreover, it is now believed that thepermanent impact of filler materials in tissue is undesired, since thetissue itself is subject to ageing (see e.g. E. Haneke, “Skinrejuvenation without a scalpel. I. Fillers”, J Cosmetic Dermatology; 5:157-167 (2005); K. De Boulle, “Management of complications afterimpantation of fillers”, J Cosmetic Dermatology; 3: 2-15 (2004).

WO-A-93/16657 teaches the use of injectable ceramic compositionscomprising biocompatible ceramic materials such as calciumhydroxyapatite in a fluid carrier. These ceramics show excellentperformance in repair and augmentation of soft and hard tissues.Further, hydroxyapatite has very low immunogenicity. The 50-250 μm sizedceramic particles are stabilized in a viscous or even gel-like organicpolymer, such as polyethylene glycol, hyaluronic acid, poly(hydroxyethylmethacrylate), or in a collagen hydrogel.

Of about the same time, WO-A-93/15721 discloses a matrix of smooth,rounded, substantially spherical, finely divided particles of calciumhydroxyapatite in a biocompatible, resorbable lubricious gel carriercomprising a polysaccharide. The particles are typically in the range of35-150 μm to minimize the possibility of particle migration byphagocytosis and to facilitate injectability. The carrier serves tofurther improve the delivery of the augmentation material by injectionto the tissue site where augmentation is desired, and is typicallyformed from water, about 25 wt % glycerin and sodium carboxymethylcellulose. It enables the ceramic particles to remain in suspensionwithout settling for an indefinite period of time until used, morespecifically at least about 6 months. U.S. Pat. No. 4,803,075 suggeststhe use of further biocompatible fluid lubricants and/or viscositymodifiers, such as glycogen, maltose and the like.

However, the use of foreign body carrier materials renders theseinjectable hydroxyapatite compositions unattractive. In the art there isa continuous need to improve biocompatible implant materials for softand hard tissue repair and augmentation, wherein the use of foreign bodymaterials is minimized or even avoided. The ideal soft tissue fillerwould be non-permanent, biocompatible, have minimal side effects, notrequire allergy testing, be easy to use/inject, be painless to inject,and be cost-effective for both the physician and the patient.

DESCRIPTION OF THE INVENTION

It is an object of the invention to provide a biocompatible compositionfor use in soft and hard tissue repair and augmentation comprising aminimal amount of foreign matters, and which composition has a lowimmunogenicity.

It is a further object of the invention to provide such a biocompatiblecomposition that, if applied in soft tissue augmentation, is resorbableover time periods of 1-2 years in a human being of about 40 years ofage. If applied in hard tissue augmentation material, it should dissolvein the human body over time, but slow enough so as to allow forreplacement with growing tissue cells.

The invention thus pertains to a biocompatible composition, suitable foruse in soft or hard tissue augmentation, wherein the composition is anaqueous suspension containing a carrier fraction of ceramic particles ofless than 15 μm and an augmentation fraction of ceramic particles of atleast 20 μm. The ceramic particles of the two fractions togetherpreferably make up for more than 95 wt %, more preferably more than 98wt % of the total solids of the composition. The invention especiallypertains to such a composition for medical use, as a therapeutic agent.

Throughout the text, particle sizes apply to the largest dimension ofthe particle, unless stated otherwise.

It is now found that it is possible to stabilize augmentation particles,independent of their size and porosity, by adding them to an aqueous gelor suspension of small, unagglomerated ceramic particles. Undesiredconventional stabilizing agents can be dispensed with.

Throughout the description and claims, the term “gel” or “suspension” isused to refer to the mix of carrier particles in water, while the term“composition” refers to the mixture of augmentation particles and theaforementioned gel or suspension. It is noted that the biocompatiblecomposition in itself may also be characterized as a suspension. In thecontext of the invention, the different wording is merely intended todistinguish between the ready-to-use composition and its precursor.

The ceramic particles preferably comprise calcium phosphate, calciumsilicate, calcium carbonate or fluorides. The ceramic material ispreferably a calcium phosphate, particularly comprising hydroxyapatite,also known as basic calcium phosphate, which is the natural mineralphase of teeth and bones. As an implant material, granularhydroxyapatite, has proven to be highly compatible in tissue. Knownhydroxyapatite derivates are included. Examples include, but are notlimited to, tetracalcium phosphate, calcium pyrophosphate, tricalciumphosphate, octacalcium phosphate, calcium fluorapatite, calciumcarbonate apatite, and combinations thereof. Other equivalentcalcium-based compositions can also be used, such as calcium carbonate,and the like. These materials are commercially available, and aselection can be made from a number of mesh sizes and porosities. Thechoice of material is regardless of the microstructure, protonationstatus of the phosphate, or extent of hydration.

While the mineral content of bone could be harvested and purified forthis purpose, the use of industrially produced calcium phosphate mineralparticles is preferable, because of its more predictable quality.

In the context of the invention, the larger particles are considered asthe “augmentation particles”, and will addressed as such from now on.These augmentation particles are suspended under aqueous conditions. Itis found that such aqueous matrix comprising augmentation particles maybe stabilized by a fraction of smaller particles of the same or anotherbiocompatible ceramic material. Stabilization is required to homogenizethe ceramic augmentation particles for an indefinite amount of time, atleast sufficiently long to allow further processing and to inject thecomposition.

Hence, the smaller ceramic particles take over the role of the lubricousgel carrier of non-ceramic materials presently applied in the art forstabilization, homogenization and lubrication purposes, and may thusbeneficially replace the conventional foreign body carrier materials orlubricants. For sake of simplicity, these smaller particles ofbiocompatible ceramic material are referred to as “carrier particles” inthe context of the invention. These may be applied in compositions foreither soft or hard tissue augmentation, which compositions mainly varyin the type, size and amount of augmentation particles present therein.The invention rests in the combination of these conventionalaugmentation materials with the carrier particles as characterized herebelow.

The use of these carrier particles as stabilizing material in abiocompatible composition in tissue augmentation is unobvious,especially since it is taught in the art that small-sized augmentationmaterials would, upon injection, induce phagocytosis in the organismbody and should thus be avoided. The potential of these small particlesto homogenize and stabilize augmentation materials is nowhere mentioned.

In one embodiment, the carrier particles are preferably larger than 100nm. More preferably, these carrier particles have an average size largerthan 1 μm. Preferably, the carrier particles have a size of less than 10μm. Best results are obtained with carrier particles smaller than 5 μm.

In another embodiment, the carrier particles are preferably smaller than1000 nm, more preferably 20-500 nm, in particular 25-300 nm.

The carrier fraction preferably comprises hydroxyapatite (HA) and/orTCP. These carrier particles may be obtained from commercially availablegrades of ceramics, by conventional sieving, micronization orprecipitation from calcium nitrate and ammonium phosphate. Theprecipitate may be spray dried and/or sintered (i.e. calcinated).Alternatively, the precipitate may be processed by centrifugation andoptional sifting. Where the desired particles are obtained by sieving,this may be performed by “wet” or “dry” sieving. The particle size ispredominantly determined by the selection of the starting material.Sieving and precipitation techniques are equally well applicable. Wherea softer gel of augmentation particles is desired, it is preferred touse carrier particles as obtained by precipitation.

Since the carrier particles contribute to the stability of thecomposition through their surface properties, it is preferred that morethan 50%, preferably more than 75%, most preferably more than 90% of thetotal volume of particles in the carrier fraction is in singular orunagglomerated form. Agglomeration would only hamper the particles inachieving stability in the composition. It is thus preferred to subjecta suitable source of carrier particles to a kind of “unagglomeration”treatment, for instance by subjecting the particles to a ball milling.This is in contrast to the augmentation particles, which could be formedby an agglomeration process.

The stability of the suspension may be further improved selecting thematerial for the smaller particles on the basis of its interfacialproperties, which may be fine-tuned by the preparation route. Sinceaugmentation and carrier particles are present for different reasons,these materials do not necessarily have to be of the same origin. Infact, a selection of different materials may lead to better results,provided that the augmentation and carrier particles are chosen from theabove-listed biocompatible materials.

As aforementioned, the augmentation particles are in essence indifferentfrom those traditionally applied in bone repair and in soft tissueaugmentation. The preferred ceramics for use as augmentation particlescomprises HA, fluorapatite, octacalcium phosphate and TCP.

Especially when used in soft tissue augmentation, the augmentationparticles comprise smooth and substantially rounded particles. Theseparticles are preferably substantially spherical. “Substantiallyspherical” generally means a shape that is spheroidal. When viewing anycross-section of the particle, the difference between the average majordiameter and the average minor diameter is less than 20%.

Where lower resorbability rates are desired, it is preferred that theaugmentation materials resemble perfect spheres, because of the optimumarea-to-volume ratio and the positive effect on prevention ofinflammations related therewith. The terms “rounded” or “smooth” as usedherein refers to the fact even though the present particles are notperfect spheres, they do not have any sharp or angular edges, in orderto improve injectability if so required. Surface milling and the likecan improve surface smoothness.

The augmentation particles must be sufficiently large so as to avoidrapid degradation. Resorbtion occurs where smaller particles on theorder of 15 μm or less become engulfed by the cells and removed by thelymphatic system from the site where the augmentation material has beenintroduced into the tissues. The augmentation particles will dissolveover time, for HA typically at a rate of 15 μm/year. The resorbtion timeof the injected mass depends on the actual particle size.

The upper limit of the augmentation particles is determined by its use,being in soft or hard tissue augmentation. For soft tissue augmentationpurposes it is desired that the composition is injectable, meaning thatthe composition can easily be injected through a syringe intradermallyor subcutaneously. If introduced into soft tissue by injection the upperlimit of the particle size will be dictated by the particular injectionequipment employed. That is, the particles must be sufficiently small soas to avoid aggregation and clogging of the syringe when being injected.A typical range for injection is from about 20 to 100 μm, morepreferably from 25-50 μm.

Where injectability is an issue, it is preferred to use a narrow or evenequivalent particle size range of augmentation particles due to the factthat a distribution of such smooth and round particles reduces friction,and facilitates the ease of injecting the particles by needle from asyringe into the skin tissue at the desired augmentation site. This isin contrast to the use of the more porous, textured, irregularly shapedparticles which tend to increase the frictional forces, and are muchmore difficult to deliver by injection. Hence, it is preferred that thesize difference between the largest and the smallest (soft tissue)augmentation particle does not exceed about 35 μm. Further, it may bedesirable to minimize surface porosity to below 30%; with elimination ofjagged irregular surfaces, the ability of the smooth round particles toflow easily in contact with each other is maximized.

If the composition is to applied in bone repair, injectability is not anissue per se, since it may be applied there in other forms. Then, theaugmentation particles are preferably much larger, typically between 100μm and 4 mm, preferably between 1-1.5 mm. In hard tissue augmentationthe surface porosity plays a more critical role. It is typically morethan 30%, more preferably at least 50%, in order for the composition toprovide a matrix for the ingrowth of new cartilage and bone.

The augmentation particles and carrier particles are preferably presentin the composition in a weight ratio of 0.5:1 to 15:1, more preferablyup to 10:1. In case of soft tissue augmentation material, the weightratio is even more preferably higher than 2:1, most preferably 4:1 to9:1. These ceramic particles preferably form the only source ofaugmentation materials present in the composition. The compositionshould contain a sufficient volume of the larger ceramic particles (i.e.the augmentation particles) to provide an effective base for autogeneoustissue growth. In case of a composition for use in soft tissue repair,preferably 20-40 vol % of the total composition is formed fromaugmentation particles. In hard tissue repair, these numbers may behigher, since the augmentation particles are much larger, and may stillbe stabilized using corresponding amounts of water and carrierparticles. There, it is preferred that the amount of augmentationparticles is 10-60 vol % of the composition.

Since stabilization of the suspension is only achieved for distinct sizedistributions of small and large ceramic particles, it is essential thatthe biocompatible composition contains little amount of ceramicparticles having a size in between that of the augmentation particlesand carrier particles. It is preferred that the composition isessentially free from biocompatible ceramic particles having a sizeoutside the aforementioned ranges. However, from a practical perspectiveit should be understood that “essentially free from other biocompatibleceramic particles” means that small amounts of particles outside thedesired ranges is allowed for in the composition, preferably less than10 wt %, more preferably less than 5 wt % of the total amount of ceramicparticles.

Additionally or alternatively, it is preferred that the suspension is amultimodal distribution, preferably a bimodal distribution of ceramicparticles, containing at least a mode of augmentation particles and amode of carrier particles with one or more of the foregoingcharacteristics.

The composition is free from any resorbable lubricants as described inthe art, especially from polysaccharides such as carboxymethylcelluloseor equivalents thereof, and glycerin. Advantageously, the composition isfree from any foreign body material conventionally applied asaugmentation material or lubricant or carrier thereof. In the mostpreferred embodiment, all augmentation material present in theinjectable biocompatible composition is a form of calcium phosphate.

In addition to the augmentation material, the composition may optionallycomprise an amount of active ingredients. These active ingredients caninclude substances that may provide therapeutic effects to the processof augmentation or biological or physiological responses to the dermalaugmentation. An example of such therapeutic agent is ananti-inflammation agent that prevents or reduces the effect ofinflammations associated with dermal augmentation, an anti-bacterial,anti-fungal or anti-histamine agent. It may also involve cell adhesionpromoters, which enhance the adhesiveness of cells to the surface of theparticles. Another suitable active ingredient is a local anaestheticagent. For the purpose of osteogenesis, the ceramic filler of theinvention may be admixed with an osteoinductive factor (OFE), consideredas one of the active ingredients optionally included in the composition.OFE useful in the composition of the invention is known to the personskilled in the art. The skilled person can easily recognize whetheringredients of the composition are included for augmentation or otherpurposes.

In a preferred embodiment, the biocompatible composition of theinvention contains 25-70 wt % water, 75-30 wt % of the biocompatibleceramic materials, and optionally up to 5 wt % of active ingredients. Ifactive ingredients are present, the sum of water, carrier particles,augmentation particles and active ingredients is 100 wt %.

The invention also pertains to the method of manufacturing thebiocompatible composition of the invention. The composition ispreferably prepared by mixing the augmentation particles and carrierparticles and water at ambient conditions until all components aresuspended. Therein, it is preferred that the carrier particles aresuspended prior to or simultaneously with the augmentation particles.

Thereto, an aqueous suspension or gel of carrier particles is firstprepared, containing 10-55 wt %, preferably 15-45 wt %, more preferably20-35 wt % of carrier particles. Hence, the invention also pertains toan aqueous suspension or gel of carrier particles with theaforementioned characteristics, and the use thereof for stabilization ofaugmentation materials.

From a rheological point of view, the suspension may be characterized asbeing a thixotropic non-Newtonian liquid. In the literature, where forinstance in U.S. Pat. No. 5,922,025 in relation to conventionalglycerin-containing cellulose-polysaccharide gels containingaugmentation material mention is made of a minimum gel viscosity ofabout 20,000 mPa·s. According to U.S. Pat. No. 5,922,025, at lowervalues the particles do not remain in suspension. However, with thecarrier particles of the invention, it is possible to prepare asuspension having a viscosity as low as 5,000 mPa·s, and which iscapable of stabilizing the biocompatible composition. Obviously, theupper limit is not particularly limited, but may be adapted to theintended use. If the composition is to be injected for soft tissuerepair, it is preferred that the gel viscosity is smaller than 30,000mPa·s. For hard tissue repair there does not appear to be suchrestriction.

The aqueous composition thus obtained may be sterilized by means knownin the art, among which, favorably, gamma radiation. This adds anadditional advantage to the composition of the invention over theaqueous gels of corresponding augmentation ceramic materials in a matrixcontaining polysaccharides and/or glycerine known in the art, which aresaid to be destroyed upon gamma sterilization. Hence, with the presentcomposition sterilization is no longer limited to autoclaving.

The biocompatible composition may be used for regeneration of hardtissues, such as bone, cartilage, connective tissues and the like. Thematerials may even be formed into implants. The methods for utilizingthe composition of the invention in the repair of bones, includingsurgical methods of implanting, are well understood in the art, and thecompositions of the invention are useful in employing these standardmeans.

However, in the preferred embodiment the composition of the invention isapplied in soft tissue augmentation. Hence, the present inventionencompasses the use of the biocompatible compositions to treat skindeficiencies caused by diseases such as acne, cancer and lipodystrophysyndrome. Further, the invention encompasses the treatment of scars onor within the skin caused by accidents, wounds and injuries. The skindeficiencies may also be the result of the treatment of a disease. Thedermal augmentation method of the invention is also suitable for thetreatment of skin contour deficiencies, which are often caused by aging,environmental exposure, weight loss, child bearing, injury and surgery.

Suitable for the treatment by the method of the present invention arecontour deficiencies such as frown lines, worry lines, wrinkles, crow'sfeet, marionette lines, stretch marks, and internal and external scarsresulted from injury, wound, bite, surgery, or accident. The inventionworks particularly well with contour deficiencies of such areas ascheeks, nose, forehead and neck.

The biocompatible compositions may also be applied to augment internaltissues such as tissue defining sphincters in the treatment ofincontinence, and for the treatment of unilateral vocal cord paralysis.

The invention further pertains to a process of cosmetically improvingthe bodily appearance of a mammal, comprising introducing to themammal's body subcutaneously or intradermally the composition of theinvention in injectable form. The composition is preferably injected atone of the aforementioned places into the mammal's body. The mammal ispreferably a human being.

The invention also pertains to a kit for one of the aforementionedapplications, where the augmentation particles, the carrier particlesand other optional components are packaged in ready-to-use syringes, forinstance those as described above.

EXAMPLES Example 1 Gel of Precipitated Amorphous Hydroxyapatite CarrierParticles

Calcium phosphate (amorphous hydroxyapatite) particles are obtained byprecipitation from calcium nitrate and ammonium phosphate. The resultingparticles were less than 1 μm in size. After cleaning, a gel-likesuspension was obtained.

In this case, the gel contained, prior to mixing with the augmentationmaterial, 35 wt % carrier particles and 65 wt % water.

The augmentation particles were produced by spray-drying a slurry ofprecipitated calcium phosphate, as described above; and then sinteredand sieved to obtain particles of 25-45 μm.

Upon mixing of 14 ml of the gel with 18.84 g augmentation particles amix of 17.2 wt % carrier particles, 31.9 wt % water and 50.9 wt %augmentation particles was obtained. The weight ratio of augmentationparticles to carrier particles was 3:1. Carrier particles and watertogether formed 70 vol % of the stable suspension.

Example 2 Porous Augmentation Particles for Hard Tissue Augmentation

The gel obtained as described in example 1 was used.

6.25 g of the gel thus obtained was mixed with 1.20 g augmentationparticles (80% porous, 1-4 mm hydroxyapatite granulate material (CAMImplants, Leiden, the Netherlands).

The gel contained 35 wt % carrier particles and 65 wt % water, the mixcontained 29.4 wt % carrier particles and 54.5 wt % water and 16.1 wt %augmentation particles. The weight ratio of augmentation particles tocarrier particles was 0.5:1.

Example 3 Dense Augmentation Particles with a Gel of Calcinated CalciumPhosphate in Water

Calcium phosphate in spray-dried form was calcinated at about 400° C.,and then an average particle size of about 2-3 μm was obtained. Afterwashing, 20 g of these particles were suspended in 100 g water, yieldinga gel of 17 wt % carrier particles in 83 wt % water. 3.42 g of the gelwas mixed with 4.89 g augmentation particles (dense, 0.5-2 mm HAgranulate (CAM Implants). The biocompatible composition thus obtainedcontained 7.0 wt % carrier particles, 34.2 wt % water and 58.8 wt % hardtissue augmentation particles. The weight ratio of augmentationparticles:carrier particles=8:1. The mixture contained 34 vol % ofaugmentation particles, in terms of the total volume of the composition.

1. An injectable, biocompatible aqueous suspension with ceramicaugmentation particles having a size of 20 microns to 4 mm and 15-45 wt% ceramic carrier particles with 20-500 nm, wherein the sum ofaugmentation particles and carrier particles amounts to 30-75 wt % ofthe composition, said composition comprising 25-75 wt % water andoptionally at least one therapeutic agent, and wherein the weight ratioof said augmentation particles to said carrier particles in saidcomposition in a weight ratio of 0.5:1 to 10:1.
 2. The compositionaccording to claim 1, wherein said composition comprises 10-60 vol %augmentation particles.
 3. The composition according to claim 2, whereinsaid ceramic particles comprise calcium phosphate.
 4. The compositionaccording to claim 1, wherein said carrier particles have a size between100 and 500 nm.
 5. The composition according to claim 1, wherein saidcarrier particles have a size between 25 and 300 nm.
 6. The compositionaccording to claim 1, wherein the suspension is sterile.
 7. Thecomposition according to claim 1, comprising 15-38 wt % of said carrierparticles.
 8. The composition according to claim 1, wherein said carrierfraction comprises hydroxyapatite (HA) and/or tricalcium phosphate(TCP).
 9. The composition according to claim 1, wherein saidaugmentation particles have a size between 20 and 100 μm.
 10. Thecomposition according to claim 1, wherein said augmentation particleshave a size between 100 μm and 4 mm.
 11. The composition according toclaim 1, wherein said augmentation particles comprise calcium phosphate,calcium silicate, calcium carbonate or fluorides.
 12. The compositionaccording to claim 11, wherein said augmentation particles comprisehydroxyapatite (HA), fluorapatite, octacalcium phosphate and tricalciumphosphate (TCP).
 13. The composition according to claim 1, wherein saidcomposition comprises 20-40 vol % augmentation particles.
 14. Thecomposition according to claim 1, being free from resorbable lubricants.15. The composition according to claim 1, wherein said therapeutic agentis selected from at least one therapeutic substance selected from thegroup consisting of an anti-inflammation agent, an antibacterial agent,an antifungal agent, an anti-histamine agent, a cell adhesion promoter,a local anesthetic agent and an osteoinductive factor.
 16. Thecomposition according to claim 1, comprising up to 5 wt % of therapeuticagents.
 17. The composition according to claim 1, said augmentationparticles having a surface porosity of less than 30%.
 18. A method oftreatment comprising introducing to a mammal's body the compositionaccording to claim
 1. 19. The method according to claim 18, for hardtissue augmentation, and bone regeneration.
 20. An injectable,biocompatible aqueous suspension with ceramic augmentation particleshaving a size of 20 microns to 4 mm and ceramic carrier particles with20-500 nm, wherein the sum of augmentation particles and carrierparticles amounts to 30-75 wt % of the composition, said compositioncomprising 25-75 wt % water and optionally at least one therapeuticagent, wherein the weight ratio of said augmentation particles to saidcarrier particles in said composition in a weight ratio of 0.5:1 to10:1, and wherein said composition comprises 10-60 vol % augmentationparticles.
 21. The composition according to claim 20, wherein saidcomposition comprises 20-40 vol % augmentation particles.